Walentek P , Beyer T , Hagenlocher C , Müller C , Feistel K , Schweickert A , Harland RM , Blum M .

R01 GM042341 NIGMS NIH HHS , GM42341 NIGMS NIH HHS

             cilium assembly

Xla Wt + SCH28080 (Fig. 7 E)
Xla Wt + SCH28080 (Fig. 7 E)
Xla Wt + SCH28080 (Fig. 7 I)
Xla Wt + SCH28080 (Fig. S 5 B K)
Xla Wt + SCH28080 (Fig. S 5 D K)
Xla Wt + SCH28080 (Fig. S 5 F K)
Xla Wt + atp4a MO (Fig. 1 B)
Xla Wt + atp4a MO (Fig. 1 C row 1 col 2)
Xla Wt + atp4a MO (Fig. 1 C row 2 col 2)
Xla Wt + atp4a MO (Fig. 2 A)
Xla Wt + atp4a MO (Fig. 3 A B F)
Xla Wt + atp4a MO (Fig. 5 G G')
Xla Wt + atp4a MO (Fig. S 2 A)
Xla Wt + atp4a MO (Fig. S 2 B)
Xla Wt + atp4a MO (Fig. S 5 H K)
Xla Wt + atp4a MO (Fig. S 5 J K)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 A middle)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 A middle)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 A middle)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 A middle)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 A top)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 A top)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 B bottom)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 B bottom)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 B bottom)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 B top)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 B top)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 B top)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 bottom)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 bottom)
Xla Wt + atp4a MO + animal cap explant (Fig. S 3 bottom)
Xla Wt + dkk1 (Fig. 6 A-C)
Xla Wt + {dn}rbpj (Fig. 4 B E)

	Fig. 1. ATP4 is required for normal development of the embryonic epidermis. (A and B) Morphological analysis of the embryonic epidermis at stage 32 in control morpholino oligonucleotide (CoMO) (A) and atp4aMO (B) injected specimens. Knockdown of atp4a lead to defects in ciliation of multiciliated cells (MCCs, green) and reduced numbers of small secretory cells (SSCs, red), but without obvious effects on ion secreting cells (ISCs, yellow) or outer/goblet cells (blue). (C) Knockdown of atp4a attenuated foxj1 and foxa1 expression, but not foxi1 expression in the skin epidermis. Embryos were unilaterally injected with atp4aMO at the four-cell stage and assayed for foxj1/foxa1/foxi1 expression by WMISH at stage 15. Correct targeting was confirmed by co-injection of lineage tracer. Depicted embryos are derived from the same injected batch. Numbers in the right lower corner indicate frequency of phenotype (a, anterior; d, dorsal; p, posterior; st., stage; v, ventral).
	Fig. 2. Loss of ATP4 causes defects in MCCs reminiscent of foxj1 and Wnt/PCP phenotypes. (A–C) Analysis of the cellular phenotype in MCCs using high magnification confocal single cell imaging. (A) Cells were stained with an antibody against acetylated-α-tubulin (tubulin, red) and phalloidin-Alexa488 for actin staining (actin, green). Control (uninj.) MCCs were characterized by the presence of a dense ciliary tuft projecting from the apical surface (dashed lines in lateral projections) and the presence of an apical actin meshwork. In contrast, MCCs in atp4a morphants showed reduced ciliation, intracellular accumulation of tubulin and defects in the apical actin meshwork formation. (B) The localization of basal bodies to the apical membrane was analyzed using overexpression of sas6-gfp (green) in combination with tubulin (blue) staining, the outlines of the cells are depicted by the dashed lines in the apical views. Control MCCs were fully ciliated and basal bodies aligned close to the apical membrane (dashed lines in lateral projections), while atp4a morphant MCCs had severe defects in ciliation, which correlated with aberrant basal body distribution within the cell. Basal bodies in atp4a morphants were mislocalized to the deep cytoplasm and not uniformly distributed along the apical membrane. (C) Basal body orientation was analyzed using centrin4-rfp (red) and clamp-gfp (green) overexpression. In control MCCs, basal bodies were mostly uniformly aligned along the anterior–posterior axis, while this alignment was randomized in atp4a morphant embryos. Lower panels show a magnified field of basal bodies.
	Fig. 3. ATP4-dependent Wnt signaling is required for foxj1 expression and ciliation in the Xenopus embryonic skin. (A–E) Immunofluorescent analysis of skin ciliation at stage 30. Embryos were stained for tubulin (acetylated-α-tubulin, red) and actin (phalloidin-Alexa488, green) and analyzed by confocal microscopy. (B) In atp4a morphants fully ciliated, partially ciliated and non-ciliated MCCs were found. Smaller intercalating cells with ISC morphology, which are also negative for acetylated-α-tubulin staining are marked with asterisks in A and B. Note that atp4a (C), β-catenin (β-cat.; D) and foxj1 (E) DNAs partially rescued ciliation in atp4a morphants. (A‵–E‵) Lateral projections of confocal z-scans are shown in (A)–(E). (A‶–E‶) Higher magnification of representative MCCs. (F) Quantification of results (n, number of embryos; (n), number of cells).
	Fig. 4. ATP4a-dependent Wnt signaling acts downstream of Notch in skin foxj1 induction. (A–D) foxj1 was stained in uninjected control (uninj.) embryos (A), as well as manipulated embryos (injected side shown in B–D). (B) Inhibition of Notch by injection of Su(H)-DBM mRNA increased foxj1 expression, which remained dependent on ATP4a (C) and Wnt/β-catenin (β-cat.; D). (E) Quantification of results. Staining intensity on the injected (right) side was compared to the uninjected (left) control side and quantified as right/injected side stronger, weaker or equal to the control side (G) (a, anterior; d, dorsal; n, number of embryos; ns, not significant; p, posterior; st., stage; v, ventral).
	Fig. 5. Serotonin secretion and tph1 expression in the embryonic epidermis are regulated by ATP4a-mediated Wnt/β-catenin signaling. (A–D) Immunofluorescent analysis and quantification (E) of serotonin (5-HT; red) deposition in small secretory cells (SSCs) of the skin at stage 32. Actin (phalloidin-Alexa488) staining in green. (A) Uninjected (uninj.) control. (B) Loss of serotonin staining in atp4a morphants. (C,D) Rescue of serotonin staining upon co-injection of atp4a (C) or β-catenin (β-cat.; D) DNA constructs. (A‵–D‵) Serotonin channel. (A‶–D‶) Higher magnification of (A–D). (E) Quantification of results. (F–H) WMISH for tph1. (F, F‵) Uninjected control. (G, G‵) Loss of tph1 expression in atp4a morphants was rescued by co-injection of atp4a DNA (H) (n, number of embryos; st., stage).
	Fig. 6. Endogenous Wnt/β-catenin signaling is required for ciliation and serotonin signaling in the ciliated epidermis. Immunofluorescent analysis (A,B) and quantification (C) of MCC ciliogenesis (acetylated-α-tubulin, blue) and serotonin (5-HT; red) deposition in small secretory cells (SSCs) of the skin at stage 32. Actin (phalloidin-Alexa488) staining in green. (A) Uninjected (uninj.) controls are characterized by dense ciliation of MCCs (A‵) and the presence of large numbers of serotonin positive SSCs (A‶). (B) Impaired ciliogenesis and loss of serotonin staining in dkk injected specimens. dkk injected embryos showed a decrease in ciliation in MCCs (B‵) and reduced numbers serotonin stained cells (B‶) (n, number of embryos; (n), number of cells; st., stage).
	Fig. 7. Late pharmacological inhibition of ATP4 causes loss of MCCs and decreased mucociliary clearance. Immunofluorescent analysis (A–D) of MCC ciliogenesis (acetylated-α-tubulin, blue) and serotonin (5-HT; red) deposition in small secretory cells (SSCs) of the skin at stages 35 (A and B) and 41 (C and D). Actin (phalloidin-Alexa488) staining in green. Embryos were treated with DMSO as control or SCH28080 during the indicated stages. Stage 35 (A) and stage 41 (C) DMSO treated controls displayed fully ciliated MCCs (A‵, C‵) and the presence of large numbers of serotonin positive SSCs (A‶, C‶). At stage 35 no apparent defects in MCC ciliation (B‵) or SSC serotonin deposition (B‶) were observed in SCH28080 treated embryos (cf. quantification in Fig. S3K), although 50% of specimens contained MCCs with a relatively small apical surface area and 60% of specimens were abnormal in their epithelial morphology, i.e. enlarged cells were present (cf. Quantification in Fig. S3K). In contrast, SCH28080 treatment until stage 41 lead to a massive loss of MCCs (D‵), but no effect on SSCs (D‶). (E) Quantification of cilia-driven fluid flow velocities revealed a significantly reduced extracellular fluid flow at the epidermis at stages 35 and 41, as compared to DMSO treated controls of the same stage. (F and G) High-magnification confocal imaging on the same set of specimens depicted in (C and D) confirmed the lack of MCCs, but intact SSCs in SCH28080 treated embryos and further indicated apical expansion in ISC-like cells and SSCs as well as enriched actin staining at some cell junctions (G). MCCs and epithelial morphology appeared normal in DMSO treated controls (F). (H and I) Embryos were treated with DMSO or SCH28080 from stage 24–40 and foxj1 expression was analyzed by in situ hybridization. In comparison to controls (H), foxj1 staining was increased in SCH28080 treated tadpoles (I) (n, number of embryos; st., stage).
	To investigate the potential function of ATP4 in formation of the ciliated Xenopus embryonic epidermis, we analyzed the expression of ATP4a protein in the epidermal ectoderm ( Fig. S1). ATP4a was found throughout the animal hemisphere during gastrulation (Fig. S1A and A‵) and neurulation (Fig. S1B and C), within the outer and deep layer of the skin ectoderm (Fig. S1B). The deep layer forms multiciliated cells (MCCs), ion secreting cells (ISCs) and small secretory cells (SSCs) which later intercalate into the outer epithelium ( Deblandre et al., 1999; Dubaissi et al., 2014 ; Stubbs et al., 2006)⁠. Furthermore, ATP4a protein was enriched in the epidermal ectoderm during neurulation (Fig. S1C), and continued expression in the epidermis throughout tailbud (Fig. S1D) and early tadpole stages (Fig. S1F and G).
	S2 Expression of three major transcriptional regulators in MCCs was analyzed: multicilin (mci) ( Stubbs et al., 2012)⁠, myb (Tan et al., 2013)⁠ and foxj1 ( Fig. S2C). mci was only weakly expressed at stage 10, peaked at stage 19 and was barely detectable at later stages (25 and 32) of mucociliary development.
	S3 Expression of three major transcriptional regulators in MCCs was analyzed: multicilin (mci) ( Stubbs et al., 2012)⁠, myb (Tan et al., 2013)⁠ and foxj1 ( Fig. S2C). mci was only weakly expressed at stage 10, peaked at stage 19 and was barely detectable at later stages (25 and 32) of mucociliary development. The atp4a morphant explants did not display significant changes in mci expression at stages 10 and 19, but there was a slight increase at stages 25 and 32 relative to controls ( Fig. S3A). Morphant explants strongly downregulated myb and foxj1 during cell type specification and intercalation stages, but these recovered to normal or above-normal levels by stage 32 ( Fig. S3A). These results indicated that not Mci-dependent MCC specification was affected in atp4a morphants, but downstream gene expression of foxj1 and myb, which are required for MCC ciliation. SSCs are induced later during development, compared to MCCs or ISCs ( Dubaissi et al., 2014 ; Walentek et al., 2014). Accordingly, foxa1 expression was highest at stage 25 ( Fig. S3B). foxa1 expression was markedly reduced by atp4aMO injections at stages 19 and 25. Furthermore, expression of tph1 (Tryptophan hydroxylase 1; a rate-limiting enzyme for serotonin synthesis and SSC marker; Walentek et al., 2014) was strongly reduced in explants derived from atp4a morphants. In contrast, atp4a knockdown did not negatively affect foxi1 expression ( Fig. S3C).
	S4 Uniformly aligned basal bodies were found in control specimens, while the alignment was randomized in ATP4a-deficient MCCs (Figs. 2C and S4)
	S5 In addition to rescue experiments using DNA co-injection, specificity of the atp4aMO was confirmed by (a) atp4a knockdown using a second non-overlapping translation blocking MO (atp4aMO-2; Fig. S5G, H and K), (b) a splice-site MO (atp4a-SplMO; Fig. S5I–K) targeting the second exon/intron boundary of atp4a pre-mRNA, which lead to atp4a intron 2 retention as confirmed by PCR (see (Walentek et al. 2015, Fig. 4)), and (c) specific pharmacological inhibition of ATP4 using SCH28080 (Fig. S5A, B and K; Walentek et al., 2012). Each of these treatments caused MCC ciliation defects comparable to atp4aMO injections, without significant decrease in tubulin-enriched epidermal cells ( Fig. S5K). ... Our experimental results argue strongly for a role of ATP4 during development of the Xenopus mucociliary epidermis, thereby suggesting a potential role for ATP4 in mucociliary clearance in the mammalian airway epithelium as well. In contrast to our early interventions in the embryo, PPIs are administered to adult patients after development of the airway epithelium. In order to address how pharmacological inhibition of ATP4 in mature mucociliary epithelia could influence mucociliary clearance, we performed experiments in which SCH28080 was applied at different stages of epidermal development and function. Both, MCC ciliation and serotonin deposition were analyzed as readout (Figs. S5A–F and K and 7). When applied early (stage 5–30), SCH28080 incubations had essentially the same effects on MCCs and SSCs as MO-mediated knockdown of atp4a ( Figs. S5A, B, G–J and K and 3), while later application of SCH28080 during epidermal development, starting at stages 12 or 22, had statistically significant but less pronounced effects on both MCC ciliation (p<0.001; Fig. S5C–F and K) and number of SSCs (p<0.01/p>0.05; Fig. S5C–F and K). These data indicated that ATP4 mainly plays a developmental role in MCC ciliation and specification of SSCs in the embryonic epidermis. In line with this assumption, SCH28080-mediated inhibition of ATP4 starting at stage 29, i.e. when functional MCCs and SSCs were already present, did not significantly affect ciliation or serotonin deposition in MCCs and SSCs, respectively (Figs. S5K and 7A and B). Nevertheless, a quantitative analysis of extracellular fluid flow (Walentek et al., 2014) revealed significantly reduced velocities of automatically tracked fluorescent beads at stage 35 in tadpoles treated with SCH28080 from stage 29 onwards (p<0.05; Fig. 7E). Prolonged incubation of tadpoles in SCH28080-containing media until stage 41 further decreased extracellular fluid flow velocities, resulting in an almost complete loss of mucociliary clearance (p<0.001; Fig. 7E). Interestingly, tadpoles treated with SCH28080 from stage 30–41 (~72 h) displayed a massive loss of MCCs (ciliated MCCs as well as tubulin-enriched cells) in the epithelium, while serotonin-containing SSCs were not affected (Fig. 7C and D). Analysis of epidermal morphology using high-resolution confocal microscopy further revealed loss of cells containing a MCC-specific apical actin meshwork, apical enlargement of ISC-like cells as well as SSCs, and accumulations of actin at cell junctions (Fig. 7F and G). This phenotype suggested that MCCs were lost in the epithelium, leading to a decrease in apical surface tension and, therefore, allowing other intercalating cell types to expand their apical surface area.
	S6 Injection of β-catenin DNA alone did not significantly alter MCC ciliation or number of MCCs ( Fig. S6A–C), in agreement with previously published work, in which gain of canonical Wnt signaling did not increase the number of α-tubulin expressing cells in the Xenopus embryonic epidermis ( Ossipova et al., 2007).
	S7 Overexpression of β-catenin mRNA(β-cat. RNA; Fig. S7) did not consistently lead to increased numbers of MCCs or SSCs in the epidermis at stage 32 (Fig. S 7 C and D), although it is note worthy that in two out of twelve specimens a massive increase in MCCs occurred, indicating a potentially more complex relationship between canonical Wnt signaling and MCC specification. In summary, our data revealed a developmental requirement for ATP4a-dependent Wnt/β-catenin signaling during Foxj1- mediated motile ciliogenesis and Foxa1-mediated specification of SSCs in the mucociliary epidermis of Xenopus embryos.
	tph1 (tryptophan hydroxylase 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 32, lateral view, anterior right, dorsal up.
	atp6v1e1 (ATPase, H+ transporting, lysosomal 31kDa, V1 subunit E1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 32, lateral view, anterior left, dorsal up.

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